title: Chlorbipram: a novel PDE4 inhibitor with improved safety as a potential antidepressant and cognitive enhancer.
abstract: Major depressive disorder is a common, but serious, psychiatric dysfunction that affects 21% of the population worldwide. Rolipram, a first-generation phosphodiesterase-4 (PDE4) inhibitor, has been shown to have significant antidepressant and cognitive enhancement effects; however, it was unsuccessful in clinic trials because of PDE4-dependent side effects such as nausea and emesis. In this study, we investigated the neuropharmacology of the novel PDE4 inhibitor chlorbipram and the classical PDE4 inhibitor rolipram. Using antidepressant-sensitive behavioral tests, we demonstrated that the acute single administration of chlorbipram (0.075-0.6 mg/kg) produced antidepressant-like effects, as evidenced by decreases in the duration of immobility in Kunming mice in the forced swim and tail suspension tests, and no significant changes in locomotor activity. Scopolamine-induced cognitive dysfunction was also significantly attenuated in the Morris water maze test after the treatment of Sprague Dawley rats with different doses of chlorbipram (0.5-1.5mg/kg). Furthermore, we evaluated the emetic potential of chlorbipram in beagle dogs. After oral administration, 0.5mg/kg rolipram showed emetic profiles in all dogs within 20 minutes, whereas chlorbipram did not induce any emesis during the 120-min observation period, even at the 1.0mg/kg dose. Together, our data suggest that chlorbipram is a novel antidepressant and cognitive enhancer with little or no emetic potency.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR China.
authors.forename: Ming-Zi
authors.initials: MZ
authors.lastname: Zhang
authors.forename: Zhong-Zhen
authors.initials: ZZ
authors.lastname: Zhou
authors.forename: Xin
authors.initials: X
authors.lastname: Yuan
authors.forename: Yu-Fang
authors.initials: YF
authors.lastname: Cheng
authors.forename: Bing-Tian
authors.initials: BT
authors.lastname: Bi
authors.forename: Mei-Fang
authors.initials: MF
authors.lastname: Gong
authors.forename: Yu-Pin
authors.initials: YP
authors.lastname: Chen
authors.forename: Jiang-Ping
authors.initials: JP
authors.lastname: Xu
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D004285:Dogs; D005260:Female; D008297:Male; D051379:Mice; D058988:Phosphodiesterase 4 Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D011724:Pyridazines / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D012449:Safety; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000928:Antidepressive Agents; D058988:Phosphodiesterase 4 Inhibitors; D011724:Pyridazines; C000589512:chlorbipram; C062482:pyridazine; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4
keywords: Antidepressant; Chlorbipram; Cognitive enhancer; Emesis; PDE4 inhibitor